Probing the Dynamic Nature of Water Molecules and Their Influences on Ligand Binding in a Model Binding Site

Daniel Cappel, Rickard Wahlstroem, Ruth Brenk, Christoph A. Sotriffer

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    14 Citations (Scopus)

    Abstract

    The model binding site of the c-ytochrome c peroxidase (CCP) W191G mutant is used to investigate the structural and dynamic properties of the water network at the buried cavity using computational methods supported by crystallographic analysis. In particular, the differences of the hydration pattern between the uncomplexed state and various complexed forms are analyzed as well as the differences between five complexes of CCP W191G with structurally closely related ligands. The ability of docking programs to correctly handle the water molecules in these systems is studied in detail. It is found that fully automated prediction of water replacement or retention upon docking works well if some additional preselection is carried out but not necessarily if the entire water network in the cavity is used as input. On the other hand, molecular interaction fields for water calculated from static crystal structures and hydration density maps obtained from molecular dynamics simuladons agree very well with crystallographically observed water positions. For one complex, the docking and MD results sensitively depend on the quality of the starting structure, and agreement is obtained only after redetermination of the crystal structure and refinement at higher resolution.

    Original languageEnglish
    Pages (from-to)2581-2594
    Number of pages14
    JournalJournal of Chemical Information and Modeling
    Volume51
    Issue number10
    DOIs
    Publication statusPublished - Oct 2011

    Keywords

    • CYTOCHROME-C PEROXIDASE
    • ARTIFICIAL PROTEIN CAVITY
    • HYDROGEN-BOND FUNCTIONS
    • STRUCTURE-BASED DESIGN
    • ACTIVE-SITE
    • DRUG DESIGN
    • HIV PROTEASE
    • CRYSTALLOGRAPHIC ANALYSIS
    • RECEPTOR FLEXIBILITY
    • CRYSTAL-STRUCTURES

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